Gamma/delta (gd) T cells are specialized immune cells that are thought to be a first line of defense against major infections. They are known to be activated early during infections such as tuberculosis, malaria, and bacterial meningitis. gd T cells recognize and respond to infectious agents using a receptor (the gd antigen receptor, or gd TCR) on their surface, which binds to parts of infecting organisms (antigens) or other molecules on infected cells that indicate their presence. In addition to recognition of invading organisms by the gd TCR, other 'costimulatory' and 'accessory' surface receptors cooperate to generate biochemical signals to activate the cell. This results in the release of proteins that kill infecte cells (eg. perforin), as well as soluble factors (eg. cytokines IFNg and IL-17) that attract other types of immune cells, such as neutrophils and conventional ab T cells, to sites of infection and inflammation. Surprisingly little is known about how the gd TCR, along with associated accessory and costimulatory receptors, work to activate the cell. These molecular interactions, which together form the basis for antigen recognition, is thought to take place at a specialized junction that forms between gd T cells and infected cells known as the immunological synapse, but how it is organized and functions is unclear. It also seems that gd T cells must recognize components of infecting organisms when they are bound to other 'presenting' molecules on the cell surface. However, the identity of these molecules and the strategies used by gd TCRs to recognize them, remain obscure. These uncertainties about how gd T cells recognize and are activated by infections present major impediments to their effective harnessing in treatments and vaccination strategies targeting these diseases. I aim to understand the molecular underpinnings of gd T cell function using advanced in vitro and in vivo imaging technologies, to identify mechanisms of immune activation in these cells that are critical for their role in responding to infections. This work will lead to a more detailed understanding of these medically relevant immune cells, and may contribute to the design of strategies to enhance our immune defenses by boosting gd T cell function. Public Health Relevance: Gamma/delta (gd) T lymphocytes are specialized immune cells that are a first line of defense against major infections and malignancies. Surprisingly little is known about how they function, which hampers their effective exploitation in therapies targeting these diseases. I aim to understand the molecular underpinnings of gd T cell function with the ultimate goal of using this knowledge to enhance our immune defenses by boosting their function.